mangostin and Triple-Negative-Breast-Neoplasms

Triple-negative breast cancer (TNBC) does not express estrogen receptor, progesterone receptor, and human epidermal growth factor receptor; therefore, TNBC lacks targeted therapy, and chemotherapy is the only available treatment for this illness but causes side effects. A putative strategy for the treatment of TNBC could be the use of the polyphenols such as α-Mangostin (α-M), which has shown anticancerogenic effects in different cancer models and can modulate the inflammatory and prooxidant state in several pathological models. The redox state, oxidative stress (OS), and oxidative damage are highly related to cancer development and its treatment. Thus, this study aimed to evaluate the effects of α-M on redox state, mitochondrial metabolism, and apoptosis in 4T1 mammary carcinoma cells. We found that α-M decreases both protein levels and enzymatic activity of catalase, and increases reactive oxygen species, oxidized proteins and glutathione disulfide, which demonstrates that α-M induces oxidative damage. We also found that α-M promotes mitochondrial dysfunction by abating basal respiration, the respiration ligated to oxidative phosphorylation (OXPHOS), and the rate control of whole 4T1 cells. Additionally, α-M also decreases the levels of OXPHOS subunits of mitochondrial complexes I, II, III, and adenosine triphosphate synthase, the activity of mitochondrial complex I as well as the levels of peroxisome proliferator-activated receptor-gamma co-activator 1α, showing a mitochondrial mass reduction. Then, oxidative damage and mitochondrial dysfunction induced by α-M induce apoptosis of 4T1 cells, which is evidenced by B cell lymphoma 2 decrease and caspase 3 cleavage. Taken together, our results suggest that α-M induces OS and mitochondrial dysfunction, resulting in 4T1 cell death through apoptotic mechanisms.

Topics: Apoptosis; Humans; Mitochondria; Oxidative Stress; Reactive Oxygen Species; Triple Negative Breast Neoplasms

Triple-negative breast cancer (TNBC) is a very aggressive subtype of breast cancer characterized by drug resistance and distant metastasis. Cancer stem cells (CSCs) are considered a major contributor to TNBC's drug resistance. Thus targeting and eliminating CSCs have been vigorously researched. However, the precise targetable molecular networks responsible for CSC genesis remain unclear; this conundrum is mainly due to the high heterogeneity of the TNBC tumor microenvironment (TME). The cancer-associated fibroblasts (CAFs) are one of the most abundant cellular components of the TME. Emerging studies indicate that CAFs facilitate TNBC's progression by establishing a pro-tumor TME. Hence, identifying the molecular networks involved in CAF transformation and CAF-associated oncogenesis are essential areas to be explored. Through a bioinformatics approach, we identified INFG/STAT1/NOTCH3 as a molecular link between CSCs and CAF. DOX-resistant TNBC cell lines showed increased expression of INFG/STAT1/NOTCH3 and CD44 and were associated with increased self-renewal ability and CAF-transformative ability. Downregulation of STAT1 significantly reduced the tumorigenic properties of MDA-MB-231 and -468 cells and their CAF-transforming potential. Our molecular docking analysis suggested that gamma mangostin (gMG), a xanthone, formed complexes with INFG/STAT1/NOTCH3 better than celecoxib. We then demonstrated that gMG treatment reduced the tumorigenic properties similarly observed in STAT1-knocked down conditions. Finally, we utilized a DOX-resistant TNBC tumoroid-bearing mouse model to demonstrate that gMG treatment significantly delayed tumor growth, reduced CAF generation, and improved DOX sensitivity. Further investigations are warranted for clinical translation.

Topics: Animals; Cancer-Associated Fibroblasts; Cell Line, Tumor; Doxorubicin; Humans; Mice; Molecular Docking Simulation; Receptor, Notch3; STAT1 Transcription Factor; Triple Negative Breast Neoplasms; Tumor Microenvironment